The study of autoimmune diseases such as Type 1 diabetes (T1D) has been limited by the incomplete fidelity of animal models. Studies in patients have been limited by lack of access to lymphocytes from disease sites and by patient heterogeneity with respect to disease duration, treatments, genetic backgrounds and environmental triggers. Thus, high levels of scatter are seen in immunologic assays and underlying pathophysiologic mechanisms remain obscure. We have developed a Personalized Immune (PI) humanized mouse model that overcomes these limitations by allowing synchronized de novo development, in immunodeficient mice, of highly functional human immune systems from hematopoietic stem cells (HSCs) of T1D patients and healthy controls. T cells develop, from progenitors in patient CD34+ cells, in T cell-depleted, partially HLA-matched human fetal thymus tissue grafts. We now propose to develop this model further to explore the potential for stem cell-derived beta cell islet replacement therapy in the context of an autoimmune T1D-derived human immune system. Induced pluripotent stem cell (iPSC)-derived beta cells could potentially allow autologous islet replacement in diabetic patients and also have utility in modeling T1D in humanized mice. However, there is currently no information about the potential immunogenicity of these cells compared to normal adult pancreatic islet beta cells in the presence of autoimmunity. T1D-associated genetic polymorphisms expressed by beta cells themselves may contribute to disease susceptibility. We will develop a model comparing immunogenicity of healthy control-derived and T1D-derived beta cells in the presence of an autoimmune autologous immune system. Moreover, stem cell-derived beta cells may also have utility as an off-the-shelf product for allogeneic transplantation, necessitating exploration of their immunogenicity in an allogeneic context. Additionally, the impact of autoimmunity on rejection of allogeneic natural or stem cell-derived beta cells requires assessment. We have now generated iPSCs and differentiated beta cells from skin fibroblasts of the same T1D patient and healthy control volunteers donating bone marrow for construction of PI mice. We propose to: 1) Further develop this model to induce beta cell autoimmunity; and 2) Use this model to compare the immunogenicity of iPSC-derived beta cells vs natural beta cells used as islet replacement therapy in the context of both anti-beta cell autoimmunity and alloimmunity. These studies will establish important models for understanding T1D pathogenesis, using stem cell-derived beta cells to model immunotherapies and optimizing the potential of stem cell-derived beta cell therapy to replace islets in T1D.